Affiliations: Brain Disease Biomarker Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden | Molecular Neuromodulation, Department of Experimental Medical Science, Lund University, Lund, Sweden | Neural Plasticity and Repair, Department of Experimental Medical Science, Lund University, Lund, Sweden | Institute of Neurology, Department of Neurodegenerative Disease, UCL, London, UK
Note:  Correspondence to: Anna Magnusson-Lind, Wallenberg Neuroscience Center, BMC A10, SE-221 84 Lund, Sweden. Tel.: +46 462228516; Fax: +46 462220531; E-mail: [email protected]
Abstract: Background: In addition to classical neurological symptoms, Huntington's disease (HD) is complicated by peripheral pathology, including progressive skeletal muscle wasting, and common skeletal muscle gene expression changes have been shown in HD mice and human HD. Objective: To highlight possible mechanisms underlying muscle wasting in HD, we examined gene expression in pathways governing skeletal muscle contractility, skeletal myogenesis, skeletal muscle wasting, apoptosis and the NFκB signaling pathway in two HD mouse models (the transgenic R6/2 and full-length knock-in Q175). In addition, we assessed circulating markers that increase in response to skeletal muscle injury, skeletal Troponin I (sTnI), fatty acid binding protein 3 (FABP3), and Myosin light chain 3 (Myl3). Methods: We measured gene expression in muscle tissue as well as in cultured primary myocytes using qPCR. Concentrations of cytokines and muscle proteins were obtained using multiplex ELISA. Results: Circulating markers of muscle injury (sTnI, FABP3, and Myl3) were significantly increased in mouse serum. In skeletal muscle, we observed reduced gene expression of components involved in muscle contractility, with pronounced downregulation of Acta1, Myh2 and Tnni2, among others. Alongside, we found increased expression of caspases (3 and 8) and key elements of the NFκB signaling pathway, p65/RelA, Tradd, and TRAF5. We also found similar gene expression alterations in cultured primary myocytes from R6/2 mice stimulated with TNF-α. Conclusions: Our results indicate that activation of apoptotic and NFκB pathways occur alongside down-regulation of key compartments of the muscle contractility unit in skeletal muscle of HD mice, and muscle atrophy could possibly be a source of circulating disease progression markers.